rs4103

Positions:

• chr13-110445879-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001846.4(COL4A2):​c.1008C>T​(p.Pro336=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 1,613,490 control chromosomes in the GnomAD database, including 227,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18597 hom., cov: 32)
  • Exomes 𝑓: 0.53 (208570 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.347

Genes affected

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 13-110445879-C-T is Benign according to our data. Variant chr13-110445879-C-T is described in ClinVar as [Benign]. Clinvar id is 311117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110445879-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A2	NM_001846.4	c.1008C>T	p.Pro336=	synonymous_variant	17/48	ENST00000360467.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A2	ENST00000360467.7	c.1008C>T	p.Pro336=	synonymous_variant	17/48	5	NM_001846.4	P1
COL4A2	ENST00000650540.1	c.1008C>T	p.Pro336=	synonymous_variant	17/18
COL4A2	ENST00000617564.2	c.267C>T	p.Pro89=	synonymous_variant	5/10

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74703 AN: 151908 Hom.: 18579 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.495

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.484

GnomAD3 exomes AF: 0.511 AC: 127547 AN: 249516 Hom.: 33022 AF XY: 0.514 AC XY: 69578 AN XY: 135368

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.426

Gnomad EAS exome AF: 0.525

Gnomad SAS exome AF: 0.521

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.533 AC: 778336 AN: 1461464 Hom.: 208570 Cov.: 49 AF XY: 0.533 AC XY: 387803 AN XY: 727064

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.493

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.567

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.498

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.513

GnomAD4 genome AF: 0.492 AC: 74747 AN: 152026 Hom.: 18597 Cov.: 32 AF XY: 0.491 AC XY: 36457 AN XY: 74272

Gnomad4 AFR AF: 0.401

Gnomad4 AMR AF: 0.482

Gnomad4 ASJ AF: 0.450

Gnomad4 EAS AF: 0.535

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.495

Gnomad4 NFE AF: 0.543

Gnomad4 OTH AF: 0.480

Alfa AF: 0.517 Hom.: 26827

Bravo AF: 0.482

Asia WGS AF: 0.495 AC: 1723 AN: 3476

EpiCase AF: 0.530

EpiControl AF: 0.525

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Porencephaly 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.9
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4103; hg19: chr13-111098226; COSMIC: COSV64635223;